The use of electrical stimulation for treatment of medical conditions is well known. One of the most successful applications of modern understanding of the electrophysiological relationship between muscle and nerves is the cardiac pacemaker. Although origins of the cardiac pacemaker extend back into the 1800's, it was not until 1950 that the first practical, albeit external and bulky, pacemaker was developed. The first truly functional, wearable pacemaker appeared in 1957, and in 1960, the first fully implantable pacemaker was developed.
Around this time, it was also found that electrical leads could be connected to the heart through veins, which eliminated the need to open the chest cavity and attach the lead to the heart wall. In 1975 the introduction of the lithium-iodide battery prolonged the battery life of a pacemaker from a few months to more than a decade. The modern pacemaker can treat a variety of different signaling pathologies in the cardiac muscle, and can serve as a defibrillator as well (see U.S. Pat. No. 6,738,667, entitled Implantable medical device for treating cardiac mechanical dysfunction by electrical stimulation, to DENO et al). Because the leads are implanted within the patient, the pacemaker is an example of an implantable medical device.
Another such example is electrical stimulation of the brain with implanted electrodes (deep brain stimulation), which has been approved for use in the treatment of various conditions, including pain and movement disorders such as essential tremor and Parkinson's disease [Joel S. PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu. Rev. Neurosci 29 (2006):229-257].
Another application of electrical stimulation of nerves is the treatment of radiating pain in the lower extremities by stimulating the sacral nerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Li and Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic Pain Management. Anesth Analg 92(2001):505-513; U.S. Pat. No. 6,871,099, entitled Fully implantable microstimulator for spinal cord stimulation as a therapy for chronic pain, to WHITEHURST et al].
Many other forms of nerve stimulation exist [HATZIS A, Stranjalis G, Megapanos C, Sdrolias P G, Panourias I G, Sakas D E. The current range of neuromodulatory devices and related technologies. Acta Neurochir Suppl 97(Pt 1,2007):21-29]. The type of electrical stimulation that is most relevant to the present invention is vagus nerve stimulation (VNS, also known as vagal nerve stimulation). It was developed initially for the treatment of partial onset epilepsy and was subsequently developed for the treatment of depression and other disorders. The left vagus nerve is ordinarily stimulated at a location within the neck by first implanting an electrode about the vagus nerve during open neck surgery and by then connecting the electrode to an electrical stimulator circuit(a pulse generator). The pulse generator is ordinarily implanted subcutaneously within a subcutaneous pocket that is created at some distance from the electrode, which is usually in the left infraclavicular region of the chest, but it may also be implanted in a deeper pocket beneath the pectoralis major muscle. A lead is then tunneled subcutaneously to connect the electrode assembly and pulse generator. The patient's stimulation protocol is then programmed using a device (a programmer) that communicates with the pulse generator, with the objective of selecting stimulation parameters that best treat the patient's condition (pulse frequency, stimulation amplitude, pulse width, etc.) [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis, to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulation techniques for treatment of epileptic seizures, to OSORIO et al; U.S. Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders by nerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release. Neuroscience and Biobehavioral Reviews 33 (2009):1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev 29(2005):493-500; Reese TERRY, Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsy strives to improve efficacy and expand applications. Conf Proc IEEE Eng Med Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation: current concepts. Neurosurg Focus 25 (3,2008):E9, pp. 1-4; ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N. Y. Acad. Sci. 993(2003):1-13; LABINER, D. M., Ahern, G. L. Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings. Acta. Neurol. Scand. 115(2007):23-33; AMAR, A. P., Levy, M. L., Liu, C. Y., Apuzzo, M. L. J. Vagus nerve stimulation. Proceedings of the IEEE 96(7,2008):1142-1151; BEEKWILDER J P, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 27(2,2010):130-138; CLANCY J A, Deuchars S A, Deuchars J. The wonders of the Wanderer. Exp Physiol 98(1,2013):38-45].
For vagus nerve stimulators that are currently implanted in patients, the pulse generator contains a battery that powers the system. With typical stimulator settings, the battery life range may be as long as 6.6 to 10 years, but maybe as short as less than two years. Eventually the battery must be surgically replaced when it is at or near the limit of its lifetime [Depression Patient's Manual for Vagus Nerve Stimulation with the VNS Therapy System. Document REF 26-0005-6000/1, 2004. Cyberonics Inc. 100 Cyberonics Boulevard, Houston, Tex. U.S.A. 77058; VONCK K, Dedeurwaerdere S, De Groote L, Thadani V, Claeys P, Gossiaux F, Van Roost D, Boon P. Generator replacement in epilepsy patients treated with vagus nerve stimulation. Seizure 14(2,2005):89-99].
However, beginning with some of the earliest implantable systems, nerve stimulators have been developed that contain no battery whatsoever, or that use a rechargeable battery that is charged by an energy source situated outside the body of the patient. Already in 1934, CHAFFEE and LIGHT successfully stimulated the thoracic vagus nerve of an animal with an implanted electrode powered only by an externally applied electromagnetic field, as evidenced by the production of gastric acid from the animal [E. Leon CHAFFEE and Richard U. Light. A Method for the Remote Control of Electrical Stimulation of the Nervous System. Yale J Biol Med7(2,1934): 83-128]. Smaller implanted peripheral nerve and brain stimulators that had no battery were subsequently developed for use in patients in the 1960s [William W. L. GLENN, John H. Hageman, Alexander Mauro, Lawrence Eisenberg, Stevenson Flanigan, and Marvin Harvard. Electrical Stimulation of Excitable Tissue by Radio-Frequency Transmission. Ann Surg 160(3,1964):338-350; DELGADO J M. Radiostimulation of the brain in primates and man. Anesth Analg 48(4,1969):529-542]. Such systems transfer energy inductively to the implanted stimulator, from a coil outside the patient's body to an implanted coil, such that the implanted coil supplies power to the stimulator's electrodes or to an implanted rechargeable battery [U.S. Pat. No. 3,727,616, entitled Electronic system for the stimulation of biological systems, to LENKES; U.S. Pat. No. 7,813,809, entitled Implantable pulse generator for providing functional and/or therapeutic stimulation of muscles and/or nerves and/or central nervous system tissue, to STROTHER et al; U.S. Pat. No. 8,369,959, entitled Implantable medical device with integrated antenna system, to MESKENS; U.S. Pat. No. 6,782,292, entitled System and method for treatment of mood and/or anxiety disorders by electrical brain stimulation and/or drug infusion, to WHITEHURST; application US20030212440, entitled Method and system for modulating the vagus nerve (10th cranial nerve) using modulated electrical pulses with an inductively coupled stimulation system, to BOVEJA].
Such inductive systems may also be used for bidirectional telemetry of device parameter settings and physiological data, irrespective of whether the devices are also powered by induction coils [Robert PUERS and Jef Thoné. Short distance wireless communications. Chapter 7, pp. 219-277, In: H.-J. Yoo, C. van Hoof (eds.), Bio-Medical CMOS ICs. New York: Springer, 2011; U.S. Pat. No. 5,186,170, entitled Simultaneous radio frequency and magnetic field microprocessor reset circuit, to VARRICHIO et al]. Intrinsic limitations of such coil-based powering systems are that the source oscillating magnetic field must be in close proximity to the implanted pickup coil in order to transfer the energy efficiently (e.g., applied to the patient's skin), and the source and pickup coils have to be optimally oriented with respect to one another. The frequencies of oscillations for those systems involving magnetic induction are typically less than 100 MHz.
The stimulators could also be powered by ultrasound or infrared light, in which case the energy source would also likely have the disadvantage of having to be placed close to the implant [ABDO A, Sahin M, Freedman D S, Cevik E, Spuhler P S, Unlu M S. Floating light-activated microelectrical stimulators tested in the rat spinal cord. J Neural Eng 8(5,2011):056012, pp. 1-9; GULICK D W, Towe B C. Method of locating ultrasound-powered nerve stimulators. Conf Proc IEEE Eng Med Biol Soc. 2012;2012:887-890].
However, this proximity problem would not occur if the device were powered by electrochemical energy supplied by the tissue of the patient [MERCIER P, Lysaght A C, Bandyopadhyay S, Chandrakasan A P, Stankovic K M. Energy extraction from the biologic battery in the inner ear. Nat Biotechnol 30(12, 2012):1240-1243]. Energy scavenging from other sources, such as body movement, may in principle also be used for autonomous, batteryless powering [E. M. YEATMAN. Advances In Power Sources For Wireless Sensor Nodes. Proceedings of 1st International Workshop on Body Sensor Networks, London, Apr. 6-7, 2004, pp. 20-21;Joseph A. PARADISO and Thad Starner. Energy Scavenging for Mobile and Wireless Electronics. IEEE Pervasive Computing 4(1, 2005):18-27].
Another potential source of scavenged energy is ambientradio waves, e.g., as used in crystal radio sets. However, that potential source is generally limited to situations in which very little power is needed for the device, or the environment contains an unusually high level of ambient electromagnetic energy [E. M. YEATMAN. Advances In Power Sources For Wireless Sensor Nodes. Proceedings of 1st International Workshop on Body Sensor Networks, London, Apr. 6-7, 2004, pp. 20-21; Joseph A. PARADISO and Thad Starner. Energy Scavenging for Mobile and Wireless Electronics. IEEE Pervasive Computing 4(1, 2005):18-27; Rick ROBINSON. Air Power: New Device Captures Ambient Electromagnetic Energy to Drive Small Electronic Devices. Georgia Tech Research News. Research News & Publications Office. Georgia Institute of Technology, 75 Fifth Street, N.W., Suite 314, Atlanta, Ga. 30308, 2011, pp. 1-3; Vikram GUPTA, Arvind Kandhalu, Ragunathan (Raj) Rajkumar. Energy Harvesting from Electromagnetic Energy Radiating from AC Power Lines. Proceedings of the 6th Workshop on Hot Topics in Embedded Networked Sensors. Killarney, Ireland, June 2010. Article No. 17, pp. 1-5; Soheil RADIOM, Majid Baghaei-Nejad, Guy Vandenbosch, Li-Rong Zheng, Georges Gielen. Far-field RF Powering System for RFID and Implantable Devices with Monolithically Integrated On-Chip Antenna. In: Proc. Radio Frequency Integrated Circuits Symposium (RFIC), 2010 IEEE, Anaheim, Calif., 23-25 May 2010, pp. 113-116; J. H. HWANG, C. H. Hyoung, K. H. Park and Y. T. Kim. Energy harvesting from ambient electromagnetic wave using human body as antenna. Electronics Letters 49(2, 2013):149-151; MANTIPLY E D, Pohl K R, Poppell S W, Murphy J A. Summary of measured radiofrequency electric and magnetic fields (10 kHz to 30 GHz) in the general and work environment. Bioelectromagnetics 18(8,1997):563-577; FLODERUS B, Stenlund C, Carlgren F. Occupational exposures to high frequency electromagnetic fields in the intermediate range (>300 Hz-10 MHz). Bioelectromagnetics 23(8,2002):568-577].
The proximity problem would also not arise if higher-frequency beamed electromagnetic waves were used to supply power as now described. Recently, systems have been developed that power implanted pulse generators (or their rechargeable battery) using electromagnetic fields with frequencies on the order of 300 MHz to 10 GHz. An advantage of using these frequencies is that it does not ordinarily require the source of the fields be in the immediate proximity of the receiving antenna within the implanted device. For example, a horn antenna with a waveguide may be used to direct the radiation from its source to a receiving implant antenna that is several meters away from the horn. Some of these devices may operate either in the inductive mode that was described in a previous paragraph, or in the higher frequency mode wherein the electromagnetic field supplying the stimulator's power is propagated as a far-field or approximate plane wave [application US20120004708, entitled Implantable medical device and charging system employing electric fields, to CHEN et al]. Other such devices are designed to operate only at the higher frequencies. They may receive power using a rectenna, or more generally using a dipole, slot, patch, or other type of antenna that can be used to receive power at these frequencies [application US20130018438, entitled Far field radiative powering of implantable medical therapy devices, to CHOW; US20130018439, entitled Implantable nerve wrap for nerve stimulation configured for far field radiative powering, now U.S. Pat. No. 8,989,867 to CHOW; US20130018440, entitled Powering of an implantable medical therapy delivery device using far field radiative powering at multiple frequencies, to CHOW].
PERRYMAN et al also disclosed implantable neural stimulators that are powered by electromagnetic radiation at the higher frequencies, comprising one or more electrodes, a dipole antenna, and stimulation circuitry, but no internally-supplied power source. Power to the stimulator is supplied through the stimulator's dipole antenna, which is configured to receive electrical energy from a second external antenna, using electrical radiative coupling (i.e., coupling to far field or approximately plane wave radiation). That energy is then used to electrically stimulate bodily tissue adjacent to the device's electrodes, such as a peripheral nerve. The device is also configured to generate a feedback signal, which is sent from the stimulator's dipole antenna back to the second antenna, also through electrical radiative coupling. In some embodiments, an intermediate “relay module” is configured to generate the actual radiofrequency wave that is received by the implanted neural stimulator, for example, with the relay module placed under the skin over the vagus nerve in the neck [WO/2012/138782, entitled Implantable lead, to PERRYMAN et al. US20120283800, entitled Neural Stimulator System, to PERRYMAN et al. US20120330384, entitled Remote control of power or polarity selection for a neural stimulator, to PERRYMAN et al. US20130066400, entitled Microwave field stimulator, to PERRYMAN et al. US20130079849, entitled Relay module for implant, to PERRYMAN et al].
It is understood that implanted devices operating with the higher frequency electromagnetic radiation may also be used for bidirectional telemetry of device parameters or of physiological data, irrespective of whether operational power is also supplied by a transmitter operating within those frequencies. For example, telemetry may take place in the Medical Implant Communication Service band (MICS) of 402-405 MHz, and early implanted telemetry systems with a battery operated with frequencies of 100 to 500 MHz with a range of about 30 meters [DELGADO J M, Mark V, Sweet W, Ervin F, Weiss G, Bach-Y-Rita G, Hagiwara R. Intracerebral radio stimulation and recording in completely free patients. J Nerv Ment Dis 147(4,1968):329-340; Eric Y CHOW. Wireless miniature implantable devices and asics for monitoring, treatment, and study of glaucoma and cardiac disease. PhD Dissertation, West Lafayette, Ind.: Purdue University, 2009; Robert PUERS and Jef Thoné. Short distance wireless communications. Chapter 7, pp. 219-277. In: H.-J. Yoo, C. van Hoof (eds.), Bio-Medical CMOS ICs. New York: Springer, 2011].
In addition to the need to replace a battery, another disadvantage of conventional implanted vagus or peripheral nerve stimulation systems is the mechanical stress and the resulting chronic tissue response caused by the constant movement of tethering electrical cables that are connected to the pulse generator. Furthermore, the cables may break, and motion of the cables may cause their attached electrode assemblies to migrate or rotate, causing the stimulation system to fail. These problems are not unique to vagus nerve stimulators, but occur also with systems that stimulate other peripheral nerves and the spine [Konstantin V. SLAVIN. Technical Aspects of Peripheral Nerve Stimulation: Hardware and Complications. pp. 189-202 In: Konstantin V. SLAVIN (ed). Peripheral Nerve Stimulation. Progress in Neurological Surgery Vol. 24. Basel (Switzerland): Karger A G, 2011; KIM D, Vakharyia R, Kroll H R, Shuster A. Rates of lead migration and stimulation loss in spinal cord stimulation: a retrospective comparison of laminotomy versus percutaneous implantation. Pain Physician 14(6,2011):513-524]. The same may be true for the above cited-patent applications that are powered at the higher electromagnetic frequencies. The application by CHEN uses conventional cables and pulse generators, except that they may be powered by electromagnetic radiation at the higher frequencies. An above-cited application by PERRYMAN et al does not contain a separate pulse generator and tethering cables connected to the electrode assembly, but it does have a tethered “extension tubing,” with a lumen that is used with a stylet to facilitate implantation of the stimulator. In one embodiment of their invention, the system's antenna extends into the tubing [WO/2012/138782, entitled Implantable lead, to PERRYMAN et al]. After the electrodes are implanted, the tubing is shown to be left in place, and its end is anchored under the skin near the site of implant entry. Thus, the system described by PERRYMAN et al. would also cause tissue response problems, owing to the movement of the tethering tubing, for the same reason that a tethering electrical cable causes problems.
Nevertheless, there do exist implanted externally-powered nerve stimulation systems that do not contain a tethered lead or tubing after implantation. Unfortunately, however, those systems are powered externally by inductive coils, not by the higher frequency approximately plane wave or far-field electromagnetic radiation. They therefore suffer from the disadvantage that an external coil providing energy to the implanted stimulator must be very close to the implanted pickup coil in order to transfer energy efficiently. Two such systems are BION devices and microtransponder devices.
The simplest version of BION stimulators consist of wireless micromodules, each of which receives power and command signals by inductive coupling from an external antenna. Its electronic components are housed in a hermetically sealed glass capsule, which is 2 mm in diameter×16 mm in length, which is small enough to be implanted through a 12 gauge hypodermic needle. Each device delivers monophasic stimulation pulses through a tantalum capacitor electrode. The later BION versions contain a rechargeable battery that allows sufficient power for external programming and advanced telemetry. In that regard, the later BION stimulators resemble miniature stimulators that were described by WHITEHURST et al [LOEB G E, Zamin C J, Schulman J H, Troyk P R. Injectable microstimulator for functional electrical stimulation. Med Biol Eng Comput 29(6,1991):NS13-NS19; CAMERON T, Loeb G E, Peck R A, et al: Micromodular implants to provide electrical stimulation of paralyzed muscles and limbs. IEEE Trans Biomed Eng 44(9,1997):781-790; LOEB G E, Richmond F J, Baker L. The BION devices: injectable interfaces with peripheral nerves and muscles. Neurosurg Focus 20(5,2006):E2, pp. 1-9; Todd K. WHITEHURST, Joseph H. Schulman, Kristen N. Jaax, and Rafael Carbunaru. The BionMicrostimulator and its Clinical Applications. pp. 253-273. In: D. D. Zhou, E. Greenbaum (eds.). Implantable Neural Prostheses 1. Devices and Applications. New York, N.Y.: Springer-Verlag, 2009; KANE M J, Breen P, Quondamatteo F, ÓLaighin G. BION microstimulators: a case study in the engineering of an electronic implantable medical device. Med Eng Phys 33(1,2011):7-16; U.S. Pat. No. 6,735,475, entitled Fully implantable miniature neurostimulator for stimulation as a therapy for headache and/or facial pain, to WHITEHURST et al]. In one nerve stimulation application, a BION device was found to be comparable in benefit to a noninvasive nerve stimulation device, but with the noninvasive device having the advantage of not needing to be implanted [A NESBITT, J Marin, P Goadsby. Treatment of hemicrania continua by non-invasive vagus nerve stimulation in 2 patients previously treated with occipital nerve stimulation. The Journal of Headache and Pain 1(Suppl 1,2013):P230].
The BION device was developed in response to a request from the U.S. National Institutes of Health, and another such device was developed by ZIAIE and colleagues [ZIAIE B, Nardin M D, Coghlan A R, Najafi K. A single-channel implantable microstimulator for functional neuromuscular stimulation. IEEE Trans Biomed Eng 44(10, 1997):909-920; TROYK P R. Injectable electronic identification, monitoring, and stimulation systems. Annu Rev Biomed Eng 1(1999):177-209]. Subsequently, inductive micro-stimulators have been developed for additional applications [Rogier A M RECEVEUR, Fred W Lindemans and Nicolaas F de Rooij. Microsystem technologies for implantable applications. Journal of Micromechanics and Microengineering 17(5, 2007): R50-R80].
Microtransponder devices resemble human-implantable radiofrequency-identification microchips, which are powered inductively from an external electromagnetic field. They may be joined in arrays and delivered to the vicinity of a nerve through a hypodermic needle. One of their intended applications is the stimulation of a peripheral nerve [U.S. Pat. No. 7,630,771, entitled Grooved electrode and wireless microtransponder system, to CAULLER; US20050137652, entitled System and method for interfacing cellular matter with a machine, to CAULLER et al; US20090163889, entitled Biodelivery System for Microtransponder Array, to CAULLER et al; US20120296399, entitled Array of Joined Microtransponders for Implantation, to CAULLER et al; ROSELLINI W, Casavant R, Engineer N, Beall P, Pierce D, Jain R, Dougherty P M. Wireless peripheral nerve stimulation increases pain threshold in two neuropathic rat models. Exp Neurol 235(2,2012):621-626; Sung-Hoon CHO, Lawrence Cauller, Will Rosellini, and J B Lee, A MEMS-Based Fully-Integrated Wireless neurostimulator, IEEE 23rd International Conference on Micro Electro Mechanical Systems (MEMS), 24-28 Jan. 2010, Hong Kong, Proceedings pp. 300-303].
There also exists an implanted, externally-powered nerve stimulation system that does not use coils to power the implant, but it contains a tethered lead implantation, and it also requires the source of power to be applied directly to the patient's skin. It works by using a pair of noninvasive electrodes applied to the patient's skin to cause currents to flow under the skin, such that some of this current passes through electrical conductors that had been implanted in the vicinity of the nerve that is to be stimulated [Patent application US 20130013041, entitled Implant system and method using implanted passive conductors for routing electrical current, now U.S. Pat. No. 8,538,517 to GLUKHOVSKY et al.; Liu Shi GAN, Einat N. Ravid, Jan Kowalczewski, Michel Gauthier, Jaret Olson, Michael Morhart and Arthur Prochazka. First permanent human implant of the Stimulus Router System, a novel neuroprosthesis: preliminary testing of a polarity reversing stimulation technique. Conf Proc IEEE Eng Med Biol Soc. 2011:3051-3054; Timothy R. DEER, Jason E. Pope, Matthew Kaplan. A novel method of neurostimulation of the peripheral nervous system: The StimRouter implantable device. Techniques in regional anesthesia and pain management 16 (2012):113-117].
To summarize the foregoing background information, one prefers an implanted peripheral nerve stimulator (for example, a vagus nerve stimulator) that can be powered using approximately plane wave or far-field electromagnetic waves with frequencies in the range of 300 MHz to 10 GHz, so that the antenna transmitting energy for the stimulator's electrodes does not have to be placed in close proximity to the implanted stimulator in order for the stimulator to receive the energy. A related preference is that the stimulator should have simple circuitry so as to consume a small amount of power, and also so that the external transmitter can be a relatively weak power source (either inherently or because it is positioned at some distance from the implanted stimulator). One also prefers an implanted stimulator that does not have attached cables or tubes, the tethering of which would cause chronic tissue response due to movement of tethering cables. That is to say, one prefers a miniature self-contained stimulator that can be powered by external GHz plane wave or far-field electromagnetic radiation, with small power requirements. Because some such devices could be implanted with minimally invasive methods, they have additional medical and cosmetic advantages over the implantation of a conventional vagus nerve stimulator through open neck surgery. This is because the standard surgical approach to placement of vagus nerve stimulator electrodes is through an incision in the neck, approximately 4 cm in length. In patients who have difficulty with keloid and painful scar formation, and for those patients who are resistant to a neck scar for cosmetic reasons, conventional vagus nerve stimulator therapy has little appeal, regardless of its effectiveness.
The present application discloses methods for solving these problems that arise in the design and implantation of a compact, remotely-powered vagus nerve stimulator. It also discloses new methods for selecting a percutaneous path along which the vagus nerve stimulator is implanted, for performing the implantation with the aid of a robot, for attaching the implant to surrounding tissue, for repositioning or rotating the implanted stimulator if that becomes necessary, and for monitoring the safety and success of the implant procedure.